アルケン型ジペプチドイソスターの合成法の開発と生理活性ペプチドの構造活性相関研究への応用  [in Japanese] Synthesis of Highly Functionalized Alkene Dipeptide Isosteres and Its Application to the Structure-Activity Relationship Study on Bioactive Peptides  [in Japanese]

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Abstract

Peptide bonds are one of the essential contributors to overall structure and functions of bioactive peptides. The partial double-bond character derived from the resonance structure restricts the free rotation of the carbon-nitrogen bond and stabilizes the planar conformations. Additionally, the ability to form hydrogen bonds allows the stabilization of characteristic secondary structures such as α-helix and β-turn as well as the association with the receptors. Alkene dipeptide isosteres, based on the concept of ω-dihedral angle planarity, have been used as amide bond equivalents, which serve as mechanistic probes lacking amide polarity. We have developed a facile methodology for the stereoselective synthesis of highly functional dipeptide isosteres. The key reaction is the alkylation of δ-aminated α, β-enoates having an appropriate leaving group at the γ-position. Organocopper-mediated anti-S<SUB>N</SUB>2' alkylation of α, β-enoates afforded multi-substituted olefin-containing isosteres. One-pot reduction-transmetalation-alkylation of γ, γ-difluoro-α, β-enoates provided fluoroalkene dipeptide isosteres. Reduction of these substrates with organocuprate, SmI<SUB>2</SUB>, or Pd/PhSiH<SUB>3</SUB>/Et<SUB>3</SUB>N system gave Xaa-Gly-type mimetics. Similar methods were also utilized for the preparation of cis-peptide bond mimetics. The resulting isosteres and the key intermediates were studied in structure-activity relationship of bioactive peptides including integrin α<SUB>v</SUB>β<SUB>3</SUB> antagonist, chemokine receptor CXCR 4 antagonist, puberty-related GPR 54 agonist, and peptide transporter PEPT1 substrate.

Journal

  • Journal of Synthetic Organic Chemistry, Japan

    Journal of Synthetic Organic Chemistry, Japan 66(9), 846-857, 2008-09-01

    The Society of Synthetic Organic Chemistry, Japan

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Codes

  • NII Article ID (NAID)
    10024278609
  • NII NACSIS-CAT ID (NCID)
    AN0024521X
  • Text Lang
    JPN
  • Article Type
    ART
  • ISSN
    00379980
  • NDL Article ID
    9643103
  • NDL Source Classification
    ZP11(科学技術--化学・化学工業--有機化学・有機化学工業)
  • NDL Call No.
    Z17-256
  • Data Source
    CJP  NDL  J-STAGE 
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